Functional Role of Piezo1 in the Human Eosinophil Cell Line AML14.3D10: Implications for the Immune and Sensory Nervous Systems.

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, but not Piezo2 expression, in these cells, confirming the presence of the Piezo1 protein. Activation of Piezo1 with Yoda1, its specific agonist, resulted in a significant calcium influx, which was inhibited by the Piezo1-specific inhibitor Dooku1, as well as other nonspecific inhibitors (Ruthenium Red, Gd3+, and GsMTx-4). Further analysis revealed that Piezo1 activation modulated the expression and secretion of both pro-inflammatory and anti-inflammatory cytokines in AML14.3D10 cells. Notably, supernatants from Piezo1-activated AML14.3D10 cells enhanced capsaicin and ATP-induced calcium responses in the dorsal root ganglion neurons of mice. These findings elucidate the physiological role of Piezo1 in AML14.3D10 cells and suggest that factors secreted by these cells can modulate the activity of transient receptor potential 1 (TRPV1) and purinergic receptors, which are associated with pain and itch signaling. The results of this study significantly advance our understanding of the function of Piezo1 channels in the immune and sensory nervous systems.

Irisin alleviates CFA-induced inflammatory pain by modulating macrophage polarization and spinal glial cell activation.

Although the potent anti-inflammatory effects of irisin have been documented in various inflammatory disorders, its efficacy against inflammatory pain remains unexplored. Herein, we examined the therapeutic effects of irisin in a mouse model of inflammatory pain induced by complete Freund's adjuvant (CFA). Mice were divided into three groups: normal control, CFA-injected (CFA), and CFA plus irisin-treated (CFA+Irisin). The irisin-treated group exhibited a gradual reduction in mechanical allodynia and thermal hyperalgesia when compared with the CFA group. Moreover, treatment with irisin significantly upregulated the expression of M2 macrophage markers (interleukin [IL]-4 and IL-10) and downregulated M1 macrophage markers (IL-1ß, IL-6, and tumor necrosis factor-α) in the local paw tissue, dorsal root ganglion, and spinal cord tissue. However, there was no significant difference in the total number of F4/80+ macrophages in the paw tissue and dorsal root ganglion, indicating phenotypic exchange. Treatment with irisin also downregulated the expression of the glial cell activation-related markers Iba-1 and GFAP in the spinal cord tissue. To elucidate the underlying mechanisms, we detected the expression of Toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 5 (IRF5) in paw tissues, dorsal root ganglion, and spinal tissues, revealing that irisin could downregulate the expression of these proteins. Irisin alleviated inflammatory pain by modulating local tissue inflammation and peripheral and central neuroinflammation and reducing glial cell activation and M2 macrophage polarization by modulating the TLR4-MyD88-IRF5 signaling pathway. Accordingly, irisin is a promising candidate for treating inflammatory pain in various diseases.

Development of a simultaneous analytical method for the dietary exposure determination of ß-Carboline alkaloids in foods.

As ß-carboline (ßC) alkaloids, posing potential health risks, are present in a wide variety of foods, determining the exposure degrees of food to these alkaloids from dietary activity is key to ensuring food safety. Here, we developed a rapid and sensitive simultaneous analytical method for six ßC alkaloids in food. We optimized the buffered QuEChERS method, which includes a clean-up process through dispersive solid phase extraction, to extract the target compounds from food matrices; then, these compounds were detected via liquid chromatography-tandem mass spectrometry. We established calibration ranges for each target compound and matrix within the range of 0.05-250 µg/kg, and verified linearity (R2 ≥ 0.99) and limit of quantitation (≤1.63 µg/kg). Furthermore, we validated trueness (85.8%-118.8%) and precision (≤18.7%) at three levels within the calibration range, including the lowest and highest concentrations. Finally, we employed the developed method to determine the ßC alkaloid contents in 304 samples of 41 food items and dietary exposure of six ßC alkaloids resulting from daily intake. Although ßC alkaloids were detected in 86.2% of the samples, exposure level to the 41 food items was insufficient to cause toxicity.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.

GLP-1 and Its Derived Peptides Mediate Pain Relief Through Direct TRPV1 Inhibition Without Affecting Thermoregulation.

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on the transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1 and an antagonist of GLP-1, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, the exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI) in mice, without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, proposing exendin 20-29 as a promising therapeutic candidate.

Resveratrol facilitates bone formation in high-glucose conditions.

Periodontitis is known to be affected by high-glucose conditions, which poses a challenge to periodontal tissue regeneration, particularly in bone formation. In this study, the potential effects of resveratrol (3,5,4'-trihydroxystilbene, RSV) in facilitating bone formation under high-glucose conditions after periodontitis has been investigated. We focused on the analysis of osteoblasts and periodontal ligament cells, which are essential for bone formation including cell proliferation and differentiation. And we aimed to investigate the impact of RSV on bone healing, employed diabetic mouse model induced by streptozotocin and confirmed through histological observation. High-glucose conditions adversely affected cell proliferation and ALP activity in both MC3T3-E1 and hPDLF in vitro, with more significant impact on MC3T3-E1 cells. RSV under high-glucose conditions had positive effects on both, showing early-stage effects for MC3T3-E1 cells and later-stage effects for hPDLF cells. RSV seemed to have a more pronounced rescuing role in MC3T3-E1 cells. Increased ALP activity was observed and the expression levels of significant genes, such as Col 1, TGF-ß1, ALP, and OC, in osteogenic differentiation were exhibited stage-specific expression patterns. Upregulated Col 1 and TGF-ß1 were detected in the early stage, and then ALP and OC expressions became more pronounced in the later stages. Similarly, stronger positive reactions against RUNX2 were detected in the RSV-treated group compared to the control. Furthermore, in in vivo experiment, RSV stimulates the growth and differentiation of osteoblasts, thereby promoting bone formation. High-glucose levels have the potential to impair cellular functions and the regenerative capacity to facilitate bone formation with MC3T3-E1 rather than hPDLF cells. Resveratrol appears to facilitate the inherent abilities of MC3T3-E1 cells compared with hPDLF cells, indicating its potential capacity to restore functionality during periodontal regeneration.

CXCL5/CXCL8 induces neutrophilic inflammation in peri-implantitis.

OBJECTIVE AND BACKGROUND: This research aimed to examine the role of C-X-C motif chemokine ligand 5 (CXCL5) and C-X-C motif chemokine ligand 8 (CXCL8; also known as IL-8) in neutrophilic inflammation triggered by peri-implantitis and to shed light on the underlying mechanisms that link them to the development of this condition. MATERIALS: This study included 40 patients who visited the Department of Periodontology at Kyungpook University Dental Hospital. They were divided into two groups based on their condition: healthy implant (HI) group (n = 20) and peri-implantitis (PI) group (n = 20). Biopsy samples of PI tissue were collected from the patients under local anesthesia. HI tissue was obtained using the same method during the second implant surgery. To construct libraries for control and test RNAs, the QuantSeq 3' mRNA-Seq Library Prep Kit (Lexogen, Inc., Austria) was used according to the manufacturer's instructions. Samples were pooled based on representative cytokines obtained from RNA sequencing results and subjected to Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Hematoxylin and eosin staining, and immunohistochemistry (IHC) analysis were performed to visually assess expression levels and analyze tissue histology. Student's t-test was employed to conduct statistical analyses. RESULTS: Initially, heatmaps were used to examine gene expression variations between the HI and PI groups based on the results of RNA sequencing. Notably, among various cytokines, CXCL5 and CXCL8 had the highest expression levels in the PI group compared with the HI group, and they are known to be associated with inflammatory responses. In the gingival tissues, the expression of genes encoding cytokines such as interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF)-α, interleukin (IL)-6, and CXCL5/CXCL8 was assessed via RT-qPCR. The mRNA expression level of CXCL5/CXCL8 significantly increased in the PI group compared with the HI group (p < .045). Contrarily, the mRNA expression level of interleukin 36 receptor antagonist (IL36RN) significantly decreased (p < .008). IHC enabled examination of the distribution and intensity of CXCL5/CXCL8 protein expression within the tissue samples. Specifically, increased levels of CXCL5/CXCL8 promote inflammatory responses, cellular proliferation, migration, and invasion within the peri-implant tissues. These effects are mediated through the activation of the PI3K/Akt/NF-κB signaling pathway. CONCLUSIONS: This study found that the PI sites had higher gene expression level of CXCL8/CXCL5 in the soft tissue than HI sites, which could help achieve more accurate diagnosis and treatment planning.

A comprehensive review of advanced trends: from artificial synapses to neuromorphic systems with consideration of non-ideal effects.

A neuromorphic system is composed of hardware-based artificial neurons and synaptic devices, designed to improve the efficiency of neural computations inspired by energy-efficient and parallel operations of the biological nervous system. A synaptic device-based array can compute vector-matrix multiplication (VMM) with given input voltage signals, as a non-volatile memory device stores the weight information of the neural network in the form of conductance or capacitance. However, unlike software-based neural networks, the neuromorphic system unavoidably exhibits non-ideal characteristics that can have an adverse impact on overall system performance. In this study, the characteristics required for synaptic devices and their importance are discussed, depending on the targeted application. We categorize synaptic devices into two types: conductance-based and capacitance-based, and thoroughly explore the operations and characteristics of each device. The array structure according to the device structure and the VMM operation mechanism of each structure are analyzed, including recent advances in array-level implementation of synaptic devices. Furthermore, we reviewed studies to minimize the effect of hardware non-idealities, which degrades the performance of hardware neural networks. These studies introduce techniques in hardware and signal engineering, as well as software-hardware co-optimization, to address these non-idealities through compensation approaches.

Specific transcription factors Ascl1 and Lhx6 attenuate diabetic neuropathic pain by modulating spinal neuroinflammation and microglial activation in mice.

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1ß, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.

Effect of polystyrene nanoplastics exposure on gene expression and pathogenesis of zoonotic pathogen, Edwardsiella piscicida.

A surge in the number of anthropogenic pollutants has been caused by increasing industrial activities. Nanoplastics are spotlighted as a new aquatic pollutant that are a threat to microbes and larger organisms. Our previous study showed that the subinhibitory concentrations of aquatic pollutants such as phenol and formalin act as signaling molecules and modulate global gene expression and metabolism. In this study, we aimed to investigate the impact of a new type of anthropogenic contaminant, polystyrene (PS) nanoplastics, on the expression of key virulence factors in zoonotic pathogen Edwardsiella piscicida and the assessment of potential changes in the susceptibility of zebrafish as a model host. The TEM data indicated a noticeable change in the cell membrane indicating that PS particles were possibly entering the bacterial cells. Transcriptome analyses performed to identify the differentially expressed genes upon PS exposure revealed that the genes involved in major virulence factor type VI secretion system (T6SS) were down-regulated. However, the expression of T6SS-related genes was recovered from the PS adapted E. piscicida when nanoplastics are free. This demonstrated the hypervirulence of pathogen in infection assays with both cell lines and in vivo zebrafish model. Therefore, this study provides experimental evidence elucidating the direct regulatory impact of nanoplastics influx into aquatic ecosystems on fish pathogenic bacteria, notably influencing the expression of virulence factors.

TbsP and TrmB jointly regulate gapII to influence cell development phenotypes in the archaeon Haloferax volcanii.

Microbial cells must continually adapt their physiology in the face of changing environmental conditions. Archaea living in extreme conditions, such as saturated salinity, represent important examples of such resilience. The model salt-loving organism Haloferax volcanii exhibits remarkable plasticity in its morphology, biofilm formation, and motility in response to variations in nutrients and cell density. However, the mechanisms regulating these lifestyle transitions remain unclear. In prior research, we showed that the transcriptional regulator, TrmB, maintains the rod shape in the related species Halobacterium salinarum by activating the expression of enzyme-coding genes in the gluconeogenesis metabolic pathway. In Hbt. salinarum, TrmB-dependent production of glucose moieties is required for cell surface glycoprotein biogenesis. Here, we use a combination of genetics and quantitative phenotyping assays to demonstrate that TrmB is essential for growth under gluconeogenic conditions in Hfx. volcanii. The ∆trmB strain rapidly accumulated suppressor mutations in a gene encoding a novel transcriptional regulator, which we name trmB suppressor, or TbsP (a.k.a. "tablespoon"). TbsP is required for adhesion to abiotic surfaces (i.e., biofilm formation) and maintains wild-type cell morphology and motility. We use functional genomics and promoter fusion assays to characterize the regulons controlled by each of TrmB and TbsP, including joint regulation of the glucose-dependent transcription of gapII, which encodes an important gluconeogenic enzyme. We conclude that TrmB and TbsP coregulate gluconeogenesis, with downstream impacts on lifestyle transitions in response to nutrients in Hfx. volcanii.

Effects of Antibiotic Residues on Fish Gut Microbiome Dysbiosis and Mucosal Barrier-Related Pathogen Susceptibility in Zebrafish Experimental Model.

The symbiotic community of microorganisms in the gut plays an important role in the health of the host. While many previous studies have been performed on the interactions between the gut microbiome and the host in mammals, studies in fish are still lacking. In this study, we investigated changes in the intestinal microbiome and pathogen susceptibility of zebrafish (Danio rerio) following chronic antibiotics exposure. The chronic antibiotics exposure assay was performed on zebrafish for 30 days using oxytetracycline (Otc), sulfamethoxazole/trimethoprim (Smx/Tmp), or erythromycin (Ery), which are antibiotics widely used in the aquaculture industry. The microbiome analysis indicated that Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes were the dominant phyla in the gut microbiome of the zebrafish used in this study. However, in Smx/Tmp-treated zebrafish, the compositions of Fusobacteria and Proteobacteria were changed significantly, and in Ery-treated zebrafish, the compositions of Proteobacteria and Firmicutes were altered significantly. Although alpha diversity analysis showed that there was no significant difference in the richness, beta diversity analysis revealed a community imbalance in the gut microbiome of all chronically antibiotics-exposed zebrafish. Intriguingly, in zebrafish with dysbiosis in the gut microbiome, the pathogen susceptibility to Edwardsiella piscicida, a representative Gram-negative fish pathogen, was reduced. Gut microbiome imbalance resulted in a higher count of goblet cells in intestinal tissue and an upregulation of genes related to the intestinal mucosal barrier. In addition, as innate immunity was enhanced by the increased mucosal barrier, immune and stress-related gene expression in the intestinal tissue was downregulated. In this study, we provide new insight into the effect of gut microbiome dysbiosis on pathogen susceptibility.

TroR is the primary regulator of the iron homeostasis transcription network in the halophilic archaeon Haloferax volcanii.

Maintaining the intracellular iron concentration within the homeostatic range is vital to meet cellular metabolic needs and reduce oxidative stress. Previous research revealed that the haloarchaeon Halobacterium salinarum encodes four diphtheria toxin repressor (DtxR) family transcription factors (TFs) that together regulate the iron response through an interconnected transcriptional regulatory network (TRN). However, the conservation of the TRN and the metal specificity of DtxR TFs remained poorly understood. Here we identified and characterized the TRN of Haloferax volcanii for comparison. Genetic analysis demonstrated that Hfx. volcanii relies on three DtxR transcriptional regulators (Idr, SirR, and TroR), with TroR as the primary regulator of iron homeostasis. Bioinformatics and molecular approaches revealed that TroR binds a conserved cis-regulatory motif located ∼100 nt upstream of the start codon of iron-related target genes. Transcriptomics analysis demonstrated that, under conditions of iron sufficiency, TroR repressed iron uptake and induced iron storage mechanisms. TroR repressed the expression of one other DtxR TF, Idr. This reduced DtxR TRN complexity relative to that of Hbt. salinarum appeared correlated with natural variations in iron availability. Based on these data, we hypothesize that variable environmental conditions such as iron availability appear to select for increasing TRN complexity.

Heterogeneous Mean First-Passage Time Scaling in Fractal Media.

The mean first passage time (MFPT) of random walks is a key quantity characterizing dynamic processes on disordered media. In a random fractal embedded in the Euclidean space, the MFPT is known to obey the power law scaling with the distance between a source and a target site with a universal exponent. We find that the scaling law for the MFPT is not determined solely by the distance between a source and a target but also by their locations. The role of a site in the first passage processes is quantified by the random walk centrality. It turns out that the site of highest random walk centrality, dubbed as a hub, intervenes in first passage processes. We show that the MFPT from a departure site to a target site is determined by a competition between direct paths and indirect paths detouring via the hub. Consequently, the MFPT displays a crossover scaling between a short distance regime, where direct paths are dominant, and a long distance regime, where indirect paths are dominant. The two regimes are characterized by power laws with different scaling exponents. The crossover scaling behavior is confirmed by extensive numerical calculations of the MFPTs on the critical percolation cluster in two dimensional square lattices.

Effect of Electrocautery and Laser Treatment on the Composition and Morphology of Surface-Modified Titanium Implants.

The purpose of this study was to investigate the effects of different peri-implantitis treatment methods (Er,Cr:YSGG laser, diode laser, and electrocautery) on various titanium implant surfaces: machined; sandblasted, large-grit, and acid-etched; and femtosecond laser-treated surfaces. Grade 4 titanium (Ti) disks, with a diameter of 10 mm and a thickness of 1 mm, were fabricated and treated using the aforementioned techniques. Subsequently, each treated group of disks underwent different peri-implantitis treatment methods: Er,Cr:YSGG laser (Biolase, Inc., Foothill Ranch, CA, USA), diode laser (Biolase, Inc., Foothill Ranch, CA, USA), and electrocautery (Ellman, Hicksville, NY, USA). Scanning electron microscopy, energy-dispersive X-ray spectroscopy, and wettability were used to characterize the chemical compositions and surfaces of the treated titanium surfaces. Significant changes in surface roughness were observed in both the electrocautery (Sa value of machined surface = 0.469, SLA surface = 1.569, femtosecond laser surface = 1.741, and p = 0.025) and Er,Cr:YSGG laser (Ra value of machined surface = 1.034, SLA surface = 1.380, femtosecond laser surface = 1.437, and p = 0.025) groups. On femtosecond laser-treated titanium implant surfaces, all three treatment methods significantly reduced the surface contact angle (control = 82.2°, diode laser = 74.3°, Er,Cr:YSGG laser = 73.8°, electrocautery = 76.2°, and p = 0.039). Overall, Er,Cr:YSGG laser and electrocautery treatments significantly altered the surface roughness of titanium implant surfaces. As a result of surface composition after different peri-implantitis treatment methods, relative to the diode laser and electrocautery, the Er,Cr:YSGG laser increased oxygen concentration. The most dramatic change was observed after Er:Cr;YSGG laser treatment, urging caution for clinical applications. Changes in surface composition and wettability were observed but were not statistically significant. Further research is needed to understand the biological implications of these peri-implantitis treatment methods.

The Impact of Mechanical Debridement Techniques on Titanium Implant Surfaces: A Comparison of Sandblasted, Acid-Etched, and Femtosecond Laser-Treated Surfaces.

This study evaluated the effects of various mechanical debridement methods on the surface roughness (Ra) of dental implants, comparing femtosecond laser-treated surfaces with conventionally machined and sandblasted with large-grit sand and acid-etched (SLA) implant surfaces. The fabrication of grade 4 titanium (Ti) disks (10 mm in diameter and 1 mm thick) and the SLA process were carried out by a dental implant manufacturer (DENTIS; Daegu, Republic of Korea). Subsequently, disk surfaces were treated with various methods: machined, SLA, and femtosecond laser. Disks of each surface-treated group were post-treated with mechanical debridement methods: Ti curettes, ultrasonic scaler, and Ti brushes. Scanning electron microscopy, Ra, and wettability were evaluated. Statistical analysis was performed using the Kruskal-Wallis H test, with post-hoc analyses conducted using the Bonferroni correction (α = 0.05). In the control group, no significant difference in Ra was observed between the machined and SLA groups. However, femtosecond laser-treated surfaces exhibited higher Ra than SLA surfaces (p < 0.05). The application of Ti curette or brushing further accentuated the roughness of the femtosecond laser-treated surfaces, whereas scaling reduced the Ra in SLA surfaces. Femtosecond laser-treated implant surfaces, with their unique roughness and compositional attributes, are promising alternatives in dental implant surface treatments.

Memcapacitor Crossbar Array with Charge Trap NAND Flash Structure for Neuromorphic Computing.

The progress of artificial intelligence and the development of large-scale neural networks have significantly increased computational costs and energy consumption. To address these challenges, researchers are exploring low-power neural network implementation approaches and neuromorphic computing systems are being highlighted as potential candidates. Specifically, the development of high-density and reliable synaptic devices, which are the key elements of neuromorphic systems, is of particular interest. In this study, an 8 × 16 memcapacitor crossbar array that combines the technological maturity of flash cells with the advantages of NAND flash array structure is presented. The analog properties of the array with high reliability are experimentally demonstrated, and vector-matrix multiplication with extremely low error is successfully performed. Additionally, with the capability of weight fine-tuning characteristics, a spiking neural network for CIFAR-10 classification via off-chip learning at the wafer level is implemented. These experimental results demonstrate a high level of accuracy of 92.11%, with less than a 1.13% difference compared to software-based neural networks (93.24%).

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1ß, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.

Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8+ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Clinical and genetic characteristics of amyotrophic lateral sclerosis patients with ANXA11 variants.

Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant.